Are All β‐Blockers the Same? Nebivolol Vasodilator Properties and Evidence for Relevance in Treatment of Hypertension

In this issue of The Journal of Clinical Hypertension, Kandavar and colleagues1 studied the circulatory changes in prehypertensive patients by digital plethysmography for measurement of blood flow and reactive hyperemic index (RHI). Additionally, they measured augmentation index (AI) and the effect of nebivolol therapy on L-arginine, asymmetric dimethlyarginine (ADMA), symmetric dimethlyarginine (SDMA), and L-citrulline levels after 8 weeks in a blinded fashion. Consequently, they demonstrated that 8 weeks of nebivolol therapy has no significant effect on RHI, ADMA, SDMA, or AI, whereas digital blood flow and L-citrulline levels were significantly increased after nebivolol therapy. They concluded that prehypertension is associated with increased ADMA and evidence of increased arterial stiffness and preserved RHI. Nebivolol therapy is associated with digital vasodilatation and increased nitric oxide production, as depicted by increased levels of L-citrulline and mean digital blood flow.1 Nebivolol, a third-generation β1-selective β-blocker, has shown favorable effects on carbohydrate and lipid metabolism, as well as on endothelial function and oxidative stress. Nebivolol was shown to improve arterial stiffness to a greater extent than older β-blockers, increase the bioavailability of nitric oxide, decrease oxidative stress, and also have an antiproliferative effect.2-4 Thus, the current article is in accordance with previous findings in general. It is well written and has good methodology. However, some issues have to be mentioned. First, the sample size is relatively small to reach firm conclusions. Apart from that in the nebivolol group, both systolic and diastolic blood pressure (BP) also decreased in the placebo group during follow-up, suggesting that some patients may have experienced the white-coat effect. Although the authors acknowledge this and admit that they did not perform ambulatory BP monitoring, this may be the major drawback given the fact that the baseline patient number was relatively low. Second, the authors state that ADMA levels are higher when compared with those in healthy individuals but there is no mention in the manuscript regarding the levels of ADMA in this population. In addition, there was no change in ADMA before and after treatment. These findings are not novel. Indeed, the same group previously demonstrated that nebivolol treatment was associated with stable ADMA levels, while treatment with metoprolol was associated with increased ADMA levels, which is an important finding to differentiate third-generation β-blockers from older ones.5 Recent evidence has shown that central BP is more relevant for predicting cardiovascular (CV) outcomes than peripheral pressure in the brachial artery.6-8 Indeed, it was suggested that brachial BP does not reflect the pressure in the central circulation.9 In addition, different classes of antihypertensive drugs have different effects on the central BP and arterial stiffness.10 However, the current study did not show any beneficial effect of nebivolol treatment on AI despite reductions in BP.1 Vaz-de-Melo and colleagues4 demonstrated that nebivolol reduced central BP but not AI. In another study, the role of nebivolol treatment on central hemodynamics in 50 prehypertensive patients was investigated. Nebivolol achieved significant reductions in central aortic systolic, diastolic, and mean arterial BP. However, the investigators did not find a significant change in AI.11 In the same line, Eeftinck also did not demonstrate any significant effect of nebivolol on AI.12 In contrast, some recent studies showed an improvement in AI after nebivolol treatment.13-15 To make issues more complicated, a recent study showed that nebivolol did not affect AI but decreased heart rate–corrected AI.16 Thus, the literature is inconsistent with respect to AI and nebivolol and the cause of these diverse findings are unknown and need further research. However, it was suggested that AI is not simply a function of vessel stiffness but also other factors such as heart rate, vascular tone, and even height, and therefore are not a pure marker of vascular compliance.17 Thus, the effect of nebivolol on AI is a controversial issue and more studies are needed. The authors showed normal plethysmography and normal RHI and suggest that digital plethysmography is not a sensitive technique for detecting endothelial dysfunction in prehypertension. Another explanation may be disease duration. It is known that with the presence of chronic hypertension, arterial and arteriolar remodelling modifies baseline characteristics (geometry, distensibility, and structure) of reflection sites, particularly at the arteriolar level. Since the patients are at the prehypertensive stage it is possible that arterial remodelling did not occur yet, resulting in normal plethysmography and normal RHI. Last, it would be more valuable if the markers of oxidative stress and inflammation were measured before and after nebivolol treatment since prehypertension has been linked to both metabolic abnormalities and inflammation.14, 18 It is worth mentioning that β-blockers are not uniform in function. It was suggested that newer β-blockers such as nebivolol may have favorable effects on arterial stiffness and central hemodynamic parameters compared with atenolol. Indeed, previous studies have shown that β-blockers have failed to show positive effects on vascular function and central hemodynamic parameters. For this reason, it has been questioned whether β-blockers are still an appropriate therapy for uncomplicated hypertension.6, 19, 20 Since β-blockers are a heterogeneous class of drugs with different pharmacologic and physiologic properties, it may not be possible to extrapolate the results gathered from these studies using older-generation β-blockers (especially atenonol) to other drugs of the same class. Kampus and colleagues21 compared nebivolol and metoprolol in a double-blind fashion. Both drugs decreased brachial BP but central BP decreased only in the nebivolol group. These findings were similar to previous findings.10, 13 Koumaras and colleagues15 showed that central pulse pressure and AI decreased in patients taking quinapril, aliskiren, and nebivolol but did not change in those taking atenolol. The decrease in central pulse pressure and AI did not differ between patients taking quinapril, aliskiren, and nebivolol. The authors concluded that despite similar reductions in peripheral BP, atenolol is less effective than nebivolol and renin-angiotensin-aldosterone system inhibitors in improving central pulsatile hemodynamics. On the other hand, one study showed no difference between a nebivolol/hydrochlorothiazide combination and a metoprolol/hydrochlorothiazide combination on aortic wave augmentation and central BP.12 Redon and colleagues22 also showed that nebivolol produces a less pronounced impact on AI than atenolol. In another study performed in diabetic patients, it was demonstrated that nebivolol does not offer significant reductions in aortic BP over metoprolol succinate but maintains a stable metabolic profile.23 Bearing all of these issues in mind, the study by Kandavar and colleagues is an important one extending previous findings and stimulating research. More studies are needed to investigate the effect of nebivolol on various central hemodynamic parameters, inflammation, and oxidative stress in different patient populations such as prehypertensive, stage 1 hypertensive, true hypertensive, and diabetic patients. In addition, the different actions of β-blockers on different pathophysiologic mechanisms should be investigated in larger trials. The authors declare that they have no conflicts of interest.